Alkyl and alkoxy derivatives of 5, 7-dialkyl-6, 8-dioxo-5, 6, 7, 8-tetrahydro-1, 2, 3-triazino[5, 4-d]pyrimidines



niteri rates tent 3,555,?82 Patented Oct. 2, 1962 ALKYL AND ALKGXYDERIVATIVES F 5,7-DI- ALKYL fi-DIUXG 5,6,7,8 TETRAHYDRO-1,2,3-TREAZINQISA-QPYRIMIDINES Viktor Papesch, Morton Grove, Ill, assignor toG. D.

Searle & (30., Chicago, IlL, a corporation of Delaware No Drawing. FiledDec. 16, 1960, Ser. No. 76,133 8 Claims. ((31. 260-2495) The presentinvention relates to a novel group of heterocyclic compounds which arealkyl and alkoxy derivatives of5,7-dialkyl-6,8-dioXo-5,6,7,8-tetrahydro-1,2,3-triazino- [5,4-d]pyrimidines. The compounds can be represented by the following generalformula wherein pounds are3,5,7-trialkyl-4,6,8-trioxo-3,4,5,6,7,8-hexahydro-l,2,3-triazino[5,4-d]pyrimidines and 4alkoXy-S,7-dialkyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,-3-triazino[5,4-d] pyrimidines.

To prepare the compounds of this invention, an appropriate1,3-dialkyl-6-methyluracil is nitrated with a mixture of fuming nitricacid and sulfuric acid and the resultant S-nitro compound is reducedcatalytically using palladium on charcoal catalyst to give thecorresponding l,3-dialkyl--amino-6-methyluracil. Diazotization of theamine brings about ring closure and yields the corresponding5,7-dialkyl-6,8-dioXo-5,6,7,8-tetrahydro-1,2,3-triazino-[5,4-d]pyrimidine-3NoXide.

When the above compound is allowed to react with thionyl chloride atroom temperature and the product is isolated and purified underessentially anhydrous condi- 2 tions, the4-chloro-5,7-dialkyl-6,8-dioXo-5,6,7,8-tetrahydro-l,2,3-triazino[5,4-d]pyrimidineis obtained. It has the formula If, however, this product is allowed toreact with hydrochloric acid, the corresponding 5,7-dialkyl-4,6,8-dioxo-3,4,5,6,7,8-hexahydro-1,2,3-triazino[5,4-d]pyrimidine is obtained. Ithas the following structural formula Reaction of the 4-chloro compoundwith an alkali metal alkoxide such as sodium methoxide in an excess ofthe corresponding alcohol yields the corresponding 4-alkoxy- 5,7 dialkyl6,8 dioxo 5,6,7,8 tetrahydro 1,2,3 triazino[5 ,4-d] pyrimidine which hasthe following structural formula The 3-alkyl-4-oxo compounds can beprepared by reacting the5,7-dialkyl-4,6,8-trioxo-3,4,5,6,7,8-hexahydro-1,2,-3-triazino[5,4-d1pyrimidine with an alkylating agent. These compoundscan be represented by the following structural formula The compounds ofthis invention are antibacterial agents as shown by the fact that theyinhibit the growth of Diplococcus pneumoniae. The 3-alkyl-4-oxocompounds are also inhibitors of seed germination as demonstrated by aninhibition of germination of seeds of Poaceae.

The 5,7-clialkyl-4,6,8-trioxo-3,4,5,6,7,8-heXahydro-1,2,-3-triazino[5,4-d]pyrimidines are useful as intermediates in thepreparation of the 3,5,7-trialkyl-4,6,8-trioxo-3,4,-5,6,7,8-hexahydro-1,2,3-triazino [5,4-d] pyrimidines; they also act asinhibitors of seed germination as demonstrated by an inhibition ofgermination of seeds of Trifolium.

The compounds which constitute this invention and the methods for theirpreparation will appear more fully from a consideration of the followingexamples, which are given for the purpose of illustration only and arenot to be construed as limiting the invention in spirit or scope.

In these examples, quantities are indicated in parts by weight andtemperatures are expressed in degrees centigrade 0.).

Example 1 A mixture of 71.8 parts of concentrated sulfuric acid and 2.25parts of fuming nitric acid is cooled to 10 C. To this solution is addedwith stirring 12.7 parts of 1,3,6- trimethyluracil while the temperatureis maintained at 1020 C. When solution is complete, 7.8 additional partsof fuming nitric acid is added while keeping the temperature at 10-20 C.

The solution is poured onto ice and allowed to stand for 1.5 hours. Theprecipitate is filtered and washed with ice water. The solid isrecrystallized from 50% ethanol to give 1,3,6-trimethyl-5-nitrouracilmelting at about 153-154 C.

Example 2 A mixture of 36 parts of 1,3,6-trimethyl-5-nitrouracil and 3.6parts of 5% palladium on charcoal in 1000 parts of water is hydrogenatedfor 2 hours in a bomb at 7099 C. and 37-50 atmospheres. The resultantsolution is filtered, concentrated to 125 parts under reduced pressure,cooled, and filtered. This yields l,3,6-trimethyl-5-aminouracil meltingat about 169-171 C.

Example 3 A solution of 29.8 parts of l,3,6-trimethyl-5-aminoura. oil in292 parts of concentrated hydrochloric acid and 190 parts of ice isstirred and cooled to -5 C. Twentyfive parts of sodium nitrite in 41.5parts of water is slowly introduced below the surface of the aminehydrochloride solution. When the addition is complete, stirring iscontinued for an additional 1.5 hours and the mixture is allowed to warmto room temperature. The precipitate is filtered, washed with water andwith ethanol, and dried in a vacuum desiccator to give5,7-dimethyl-6,8-dioxo- 5,6,7,8-tetrahydro-1,2,3-triazino[5,4-d]pyrimidine-3N-oxide melting at about249-250" C. after recrystallization from acetic acid. It has the formulaN OHPN/ \N l CH3 Example 4 Seventy parts of5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,3-triazino[5,4-d]pyrimidine-3N-oxideand 2296 parts of thionyl chloride are stirred overnight. The excessthionyl chloride is removed under reduced pressure at a temperaturebelow 35 C. The residue is pulverized, spread on a plate and left underreduced pressure for 2 days in a vacuum desiccator. The crude materialis recrystallized twice from 5% ethyl acetate in benzene and twice frommethanol. Furthe purification gives 4-chloro-5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro 1,2,3 triazino-[5,4-d]pyrimidine melting at about 165l66 C. It has the formula \I CH3J31 Example 5 A suspension of 1.1 parts of 4-chloro-5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,3-triazino[5,4-d] pyrimidine in 39.5 partsof methanol is stirred in an ice bath. A solution of 0.25 part of sodiummethoxide in 2.4 parts of methanol is added portionwise. The mixture isstirred for 15 minutes. The precipitate is filtered and recrystallizedfrom water to yield 4-methoxy-5,7-dimethyl-6,S-dioxo-5,6,7,8 tetrahydro1,2,3 triazino[5,4-d] pyrimidine 5 melting at about 187l89 C. withdecomposition. This compound has the following structural formula 0 II NExample 6 A mixture of 15 parts of 5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydrol ,2,3-triazino [5 ,4-d] pyrimidine-3N-oxide and 246 parts ofthionyl chloride is stirred at room temperature for about 18 hours.Excess thionyl chloride is re- 20 moved under reduced pressure while thevessel is at room temperature. The residue is dissolved in 1584 parts ofbenzene. The solution is chromatographed on a column containing 800parts of silica. Elution is carried out with benzene containingincreasing amounts of ethyl acetate.

At 75% ethyl acetate, crude 4,6,8-trioxo-5,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,3 triazino[5,4-d]pyrimidine is obtained. Afterrecrystallization from ethyl acetate, the product melts at about 202203C. It has the formula CH3-N x Example 7 To a suspension of 1.6 parts of4,6,8-trioxo-5,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,3-triazino[5,4-d]pyrimidine in 15.8 parts of methanol and 8 parts of Water is added 10.6 partsof dimethyl sulfate and then 3 parts of 10% sodium hydroxide solutionportionwise with stirring. The resultant solution is concentrated to asmall volume on a steam bath. The mixture is cooled and filtered and theprecipitate is recrystallized from water to give 3,5,7-

trimethyl-4,6,8-trioxo-3,4,5,6,7,8-hexahydro-1,2,3-triazino-[5,4-d1pyrimidine melting at about 174 C. with decomposition. Thiscompound has the following formula N CH3 9) Example 8 A mixture of 59.8parts of concentrated sulfuric acid and 3 parts of fuming nitric acid iscooled in an ice bath. To this solution is slowly added With stirring12.5 parts of finely powdered 1,3-diethyl-6-methyluracil while thetemperature is maintained at l0-15 C. When solution is complete, 6.8additional parts of fuming nitric acid is added while maintaining thetemperature below 15 C.

The solution is poured onto ice and stirred to promote crystallization.The precipitate is filtered, washed with ice water and recrystallizedfrom ethanol to give l,3-diethyl-5-nitro-6-methyluracil melting at about85- 86 C.

Example 9 A mixture of 27 parts of 1,3-diethyl-5-nitro-6-methyland apressure of 34 atmospheres until no further pressure drop is noted. Theresultant mixture is filtered, and the filtrate concentrated to about 80parts under reduced pressure, cooled, and filtered to yield1,3-diethyl-5-amino- 6-methyluracil melting at about 9596 C.

Example 10 A solution of 16.8 parts ofl,3-diethyl-5-amino-6-methyluracil in 124 parts of 10% hydrochloric acidand 98 parts of crushed ice is stirred and cooled in an ice bath. Asolution of 12.1 parts of sodium nitrite in 20 parts of Water is addedslowly; a precipitate forms. Stirring is continued for 15 minutes afterthe addition is complete. The suspension is filtered and the precipitateis washed with cold water, absolute alcohol and anhydrous ether.Recrystallization from absolute alcohol yields 5,7-diethyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,3-triazino [5,4-d1pyrimi-'dine-3N-oxide melting at about 244245 C. with decomposition. It has theformula N CH3OH2-I\I/C\/\\}\T O= I l-) Example 11 A mixture of parts of5,7-diethyl-6,8-dioxo-5,6,7,8- tetrahydro-l ,2, 3-triazino- [5 ,4-d]pyrimidine-3N-oxide and 82 parts of thionyl chloride is stirredovernight at room temperature. The excess thionyl chloride is removedunder reduced pressure while the temperature is maintained below 35 C.The residual Solid is treated with 5% hydrochloric acid, warmed on asteam bath and filtered. The solid residue is treated with chloroformand a small amount of insoluble material is filtered off. The solutionis dried over sodium sulfate and evaporated to dryness. The crudeproduct is purified by repeatedly dissolving it in about 4 parts ofethyl acetate and then adding about parts of anhydrous ether. This gives4-chloro-5,7-diethyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,3-triazino[5,4-d]pyrimidine melting at about 137138 C. withdecomposition. It has the formula l o: N

N 0 JJH: .31 an.

Example 12 A mixture of 5 parts of 5,7-diethyl-6,8-dioxo-S,6,7,8-tetrahydro-1,2,3-triazino[5,4-d]pyrimidine-SN-oxide and 82 parts ofthionyl chloride is stirred overnight at room temperature. The excessthionyl chloride is removed under reduced pressure while the temperatureis maintained below 35 C. The residue is treated with 5% hydrochloricacid, warmed on a steam bath, and filtered. The filtrate is concentratedto about 10 parts under reduced pressure and filtered. The precipitateis recrystallized from 40 parts of Water to give5,7-diethyl-4,6,8-trioxo-3,4,5,6,7,8-hexahydro-1,2,3-triazin0[5,4-d]pyrimidinemelting at about 190191 C.

Example 13 To a suspension of 1 part of 5,7-diethyl-4,6,8trioxo- 0 AWEN-OHa CHsCHz-N CHzCHz What is claimed is: 1. A compound of the formula(lower alkyD-N (lower alkyl) 2.3,5,7-trimethyl-4,6,8-trioXo-3,4,5,6,7,8-hexahydro-1,-2,3-triazino-[5,4-d] pyrimidine.

3.3-methyl-5,7-diethyl-4,6,8-trioXo-3,4,5,6,7,8-hexahydro-1,2,3-triazino[5,4-d]pyrimidine.4. A compound of the formula (lower alkyl) -N i O (lower alkyl) (loweralkyl) 5. 4-methoxy-5,7-dimethyl-6,8-dioxo-5,6,7,8-tetrahydro-1,2,3-triazino[5,4-d]pyrimidine.

6. A compound of the formula wherein R and R are lower alkyl radicals.

7. 5,7-dimethyl-4,6,8-trioxo-3,4,5,6,7,8-hexahydro-1,2,3- triazino [5,4-d] pyrimidine.

8. 5,7-diethyl-4,6,8-trioXo-3,4,5,6,7,8-hexahydro-1,2,3- triazino [5,4-d] pyrimidine.

References Cited in the file of this patent UNITED STATES PATENTS Drueyet el. Feb. 16, 1960 OTHER REFERENCES Erickson et al.: The 1,2,3- and1,2,4-Triazines, Tetrazines and Pentazines, page 41, IntersciencePublishers, Inc., New York (1956).

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